This project is designed to evaluate multiple factors related to the pathogenesis of neurological diseases. Focus is currently placed on multiple sclerosis (MS). Genetic and immunological factors which contribute to the pathogenesis of this disorder are being evaluated in patients with sporadic disease and families with multiple affected members. Genes encoding HLA molecules and T-cell receptors are being compared in normal controls and individuals with MS. The cellular immune responses to myelin basic protein, proteolipid protein, and common human viruses are being evaluated in the same populations. Magnetic resonance imaging (MRI) is being used to assess the occurrence and natural history of subclinical lesions in MS. Studies using gadolinium enhancement have provided evidence that breakdown of the blood-brain barrier occurs early in the development of new lesions. To determine the frequency and natural history of such lesions, a group of patients with mild, early relapsing-remitting MS are being studied monthly. The observations from MRI investigations with gadolinium enhancement are being used to develop strategies for the future evaluation of new treatments. MRI studies are also being conducted in familial leukodystrophy and the chronic myelopathy, HTLV-I-associated myelopathy/tropical spastic paraplegia (HAM/TSP). Immunological, clinical, and MRl findings in HAM/TSP are being compared to normal carriers of HTLV-I. Patients who have high levels of cytotoxic T cells directed at HTLV-I are being treated with a high-dose, alternate day steroid regimen.